Myelinogenesis is a complex orchestration of multiple factors and cell types, including Oligodendrocytes (OLs), the myelinating cells of the CNS. The Fibroblast Growth Factor (FGF) family consists of 22 members subdivided into 7 sub-families. They act on a group of 4 Receptors (Rs), 3 of which are expressed in OLs. Our central model is that FGF signaling is an important regulator of numerous aspects of myelinogenesis, and that the developmentally-regulated, multiple responses of OLs to FGFs are due to a changing repertoire of specific FGF/FGF-R pairs, each of which contributes a subset of the overall phenotype at each stage of the lineage. Interruption of this carefully orchestrated pattern leads to myelin pathology with its attendant neurological risks. In this project period, we shall delve more deeply into the mechanisms by which this FGF system regulates specific steps in myelinogenesis and demyelinating disease. Three Specific Aims are proposed. In Aim I we study FGF-R signaling in OL development and myelin formation and maintenance. Using a series of cre/lox conditional knock-out mice with disruptions in specific FGF-R signaling, we investigate three key aspects of myelinogenesis, (1) postnatal OL differentiation and myelin assembly, (2) myelin maintenance during aging, and (3) OL progenitor generation during embryonic development. In Aim II, we study FGF/FGF-R interactions in OL-lineage cells. Using FGFs that preferentially activate specific FGF-Rs and receptor-specific blocking antibodies, we test the hypothesis that during OL lineage progression, cells are differentially activated by particular FGFs, leading to selective activation of specific, developmentally expressed FGF-Rs, eliciting stage-specific cellular responses. In Aim III, we study FGF-R function in demyelinating disease, building on the growing consensus that FGF signaling may play an important role in demyelinating disease. Using the cuprizone and lysolecithin models of de/remyelination applied to our Cre lox conditional FGF-R mutants (Aim I), we test the hypothesis that FGF- signaling in OLs, in a cell autonomous manner, is an important part of the molecular mechanism regulating the progression of demyelination, and the recovery with remyelination. The long term goal of this project is to understand the functional significance of the rigorously controlled developmental expression of FGF receptors both during OL differentiation leading to myelin biogenesis, as well as in myelin membrane function, maintenance and repair, and to apply this knowledge to an informed intervention in the treatment of demyelinating diseases such as multiple sclerosis. PUBLIC HEALTH RELEVANCE The long term goal of this project is to understand the functional significance of the rigorously controlled developmental expression of Fibroblast Growth Factor (FGF) receptors, both during oligodendrocyte differentiation leading to myelin biogenesis, as well as in myelin membrane function, maintenance and repair, and to apply this knowledge to an informed intervention in the treatment of demyelinating diseases such as multiple sclerosis and other demyelinating diseases. Clarification of the role of FGF signaling in these processes can be expected to contribute to an informed clinical intervention to encourage remyelination and/or discourage demyelination.